Pa Pat Saf Advis 2016 Dec;13(4):137-148.
Analysis of Reported Drug Interactions: A Recipe for Harm to Patients
Critical Care; Internal Medicine and Subspecialties; Nursery; Pharmacy
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Author

Matthew Grissinger, RPh, FISMP, FASCP
Manager, Medication Safety Analysis
Pennsylvania Patient Safety Authority

Abstract

Patients admitted to a hospital often receive many medications. Concomitant use of multiple medications can lead to drug interactions that occur prior to administration (i.e., drug incompatibility) or after ingestion or injection (i.e., drug-drug interaction). When an interaction occurs, the effects and characteristics of the drugs may be altered, leading to increased or decreased drug activity or new and unanticipated adverse effects. Analysts searched the Pennsylvania Patient Safety Reporting System database for reports submitted as “Medication error/Monitoring error/Drug-drug interaction” that occurred from April 2009 through March 2016. A total of 815 event reports were included in the final analysis. The most commonly reported type of drug interaction involved drug incompatibilities (41.8%, n = 341) and drug-drug interactions (27.9%, n = 227). Healthcare facilities can help reduce the opportunity for drug interactions reaching patients by addressing all areas of the medication-use process and not relying solely on the effectiveness of alerts when orders are entered into electronic health records.

Introduction

Drug interactions may occur inside (drug-drug interaction [DDI]) or outside (drug incompatibility) the body. When an interaction occurs, the pharmacological effect and/or physical characteristics of one or both drugs is altered. As a result, the pharmacological effect of one or both drugs may be increased or decreased, or a new and unanticipated adverse effect may occur.

DDIs may result from pharmacokinetic interactions (absorption, distribution, metabolism, and excretion) or from interactions at drug receptors. Often these interactions are not benign. The risk of patient harm and the potential financial burden from DDIs is significant. For example, DDIs have been estimated to account for up to 30% of all adverse drug events (ADEs).1,2 Certain patient factors (e.g., age, impaired renal function, current medications) can increase the risk and potential harm from DDIs.

A drug incompatibility occurs when two or more injectable drugs are mixed and the stability or structure of the drugs is altered by physical or chemical reactions. The resulting solution is often no longer optimal or safe for the patient. For example, physical changes to the solution may lead to precipitate formation that can cause catheter occlusion and embolism and can contribute to a range of ADEs, from thrombophlebitis to multi-organ failure. Additionally, the reduction or elimination of the active drug can lead to a therapeutic failure. The consequences of drug incompatibilities can be particularly severe in neonatal and pediatric patients. Unfortunately, inappropriate Y-site combinations (used to infuse multiple medications through one venous access point) of continuously infused drugs may be common. In an observational study of 13 intensive care units (ICUs) in Canada, the prevalence of inappropriate drug combinations was 8.5% among all patients but rose to 18.7% in patients receiving at least two continuously infused drugs.3

As the number of approved drugs increases, the risk for DDIs and drug incompatibilities increases. Pennsylvania Patient Safety Authority analysts have not previously explored drug interactions reported through the Authority’s Pennsylvania Patient Safety Reporting System (PA-PSRS). With this analysis of drug interactions reported to the Authority, analysts sought to characterize contributing factors and identify appropriate system-based risk reduction strategies to help facilities identify potential risk and minimize potential patient harm.

Methods

Analysts queried the PA-PSRS database for reports submitted as “Medication Error/Monitoring error/Drug-drug interaction” that occurred from April 2009 through March 2016. This query yielded 870 event reports. Fifty-five reports (6.3%) were excluded from final analysis because upon review of the event’s description, the error did not involve a drug interaction. A total of 815 event reports remained for final analysis.

The medication name, patient care area, event type, event description, phase(s) of the medication use process, and harm score, adapted from the National Coordinating Council for Medication Error Reporting and Prevention (NCC-MERP) harm index,4 were provided by the reporting facility. When a medication name data field was left blank or incomplete, but the name was provided in the event description, an analyst adjusted the medication name field appropriately. Reports were categorized into four categories: DDI, therapeutic duplication, contraindication, and drug incompatibility. The drug classes involved in the events also were identified. Intravenous solutions with or without electrolytes were considered to be drugs for this analysis. In the context of this analysis, therapeutic duplications are errors when two or more medications from a similar pharmacotherapeutic class and for similar indications are prescribed and/or administered to a patient. Error reports were further evaluated to identify contributing factors and potential system-based risk reduction strategies.

Results

Results were categorized by the type of drug interaction. The largest percentage of drug interaction events were drug incompatibilities (Figure 1).

Figure 1. Types of Drug Interactions Identified in Events Reported to the Pennsylvania Patient Safety Authority, April 2009 through March 2016 (N = 815)

Figure 1. Types of Drug Interactions Identified in Events Reported to the Pennsylvania Patient Safety Authority 

Drug Incompatibilities

Most of the drug incompatibility events (88.3%, n = 301 of 341) reached the patient (harm score C through I). Patient harm was noted in only 0.6% (n = 2) of the drug incompatibility reports and were reported as errors that may have contributed to or resulted in temporary harm to the patient and required intervention (harm score E; Figure 2).

Figure 2. Harm Scores of Drug Interaction Events as Reported to the Pennsylvania Patient Safety Authority, April 2009 through March 2016 (N = 815)*

Figure 2. Harm Scores of Drug Interaction Events as Reported to the Pennsylvania Patient Safety Authority * There were no reported events with harm score G, H, or I. 

More drug incompatibility events involved adult patients (41.6%, n = 142 of 341) than elderly or pediatric patients (Figure 3).

Figure 3. Age of Patients Involved in Drug Interactions, April 2009 through March 2016 (N = 815)

Figure 3. Age of Patients Involved in Drug Interactions, April 2009 through March 2016 (N = 815) 

Overall, 48 unique patient care areas were associated with a drug incompatibility event, with medical/surgical units involved in 13.2% (n = 45 of 341) of the events. Taken together, intensive care units (ICUs; e.g., cardiac ICU, neonatal ICU), where patients are often on multiple intravenous (IV) medications, were cited in 29.6% (n = 101) of reports.

Analysts reviewed event description fields to determine whether an actual incompatibility took place or whether the reported event was a “close call” (e.g., nursing identified the potential for an incompatibility before administration to the patient). Almost one out of five drug incompatibility reports (18.8%, n = 64) mentioned the formation of a precipitate and 2.1 % (n = 7) stated an infiltration took place. The largest percentage of reported events (49.3%, n = 168) described situations in which the potential for incompatibility was identified before administration (i.e., close call) and almost 30% (28.2%, n = 96) described events where two incompatible drugs were infused, but no visible precipitate formed.

Drug incompatibility reports cited 117 unique medications. The most common medications mentioned in reports included IV fluids (e.g., dextrose 5%, sodium chloride 0.9%; 16.7%, n = 57), heparin (14.4%, n = 49), pantoprazole (8.5%, n = 29), and parenteral nutrition solutions (8.5%, n = 29). The most common pairs of medications included cefTRIAXone with lactated Ringer’s solution (2.6%, n = 9) and heparin with diltiazem (2.6%, n = 9). Figure 4 shows the most common pairs of medications involved in these reported events. The most common reported pair of medications that led to actual precipitate formation was the combination of ciprofloxacin and hydration solutions with electrolytes (9.4%, n = 6 of 64).

Figure 4. Most Common Pairs in Drug-Drug Interaction Reports Identified as Drug Incompatibilities, as Reported to the Pennsylvania Patient Safety Authority, April 2009 through March 2016 (n = 341)

Figure 4. Most Common Pairs in Drug-Drug Interaction Reports Identified as Drug Incompatibilities * Accounted for more reports of precipitate formation (n = 6 of 64, 9.4%) than other drug pairs.

IV, intravenous.

Following are examples of reported errors involving patients receiving IV therapy and a precipitate occurred:*

Pentamidine mixed with NSS [normal saline solution]. Precipitate found in tubing. Medication stopped and tubing taken to pharmacy for discussion. Pentamidine found to have been mixed with NSS even though the label said it was mixed with D5 [dextrose 5%]. No indication that this impacted the patient or the IV site. Patient completed his medications and chemotherapy and went home as planned.

Patient had a piggyback line infusing Merrem® IV [meropenem] and a dose of ciprofloxacin was due. I flushed out the line after the Merrem was completed and hung the ciprofloxacin. Within five minutes after leaving the room, patient rang the call bell for assistance. Inside the tubing I noticed large amounts of whitish flakes. I disconnected and discarded the IV set and drew back [with a syringe] to withdraw medications from his port. I noticed very few white flakes in what I drew back. I then flushed the line with fluid and placed a new bag of ciprofloxacin on a new set of iv tubing and am completing the infusion. Physicians are to be notified, as well as Pharmacy.

80-year-old female patient had DOBUTamine infusion and Zosyn® [piperacillin sodium and tazobactam sodium] piggybacked via y site. The combined medications crystalized and occluded the PICC [peripherally inserted central catheter] line which had to be removed and replaced with left internal jugular central line.

Drug-Drug Interactions

DDIs accounted for 27.9% (n = 227 of 815) of reported events. Although more than half (51.5%, n= 117 of 227) of DDI events reached the patient, only 1.3% (n = 3) were reported as Serious Events (harm score E and F; see Figure 2).

Most of these events involved an elderly patient (50.7%, n = 115) while 43.2% (n = 98) involved adult patients (see Figure 3).

Forty-eight unique patient care areas were associated with a DDI event, with pharmacy cited most often (31.7%, n = 72) followed by medical/surgical units (11%, n = 25) and emergency departments (4.8%, n = 11).

There were 116 unique medications and more than 112 unique pairs of medications cited in DDI reports. The most common medications mentioned in reports included IV contrast (e.g., iohexol, iopamidol; 23.8%, n = 54), metFORMIN (23.8%, n = 54), clopidogrel (9.3%, n = 21), and simvastatin (9.3%, n = 21). The most common pairs of medications include IV contrast and metFORMIN (23.8%, n = 54), omeprazole and clopidogrel (8.8%, n = 20), and simvastatin with amiodarone (4.0%, n = 9).

Analysts queried event descriptions to determine whether alerts were mentioned or involved in the event and found that only 5.3% (n = 12 of 227) of the reports mentioned “alert,” “flag,” or “warning.”

Following are examples of reported drug interactions that reached patients:

A patient taking metFORMIN was admitted for a cardiac catheterization with contrast. MetFORMIN was not addressed on admission or discharge and was not ordered as inpatient. Discharged the next day. Instructions given to patient had no information for the patient on whether or when to resume [the metFORMIN]. The patient presented [approximately two weeks later] with myopathy, renal failure, and serum creatinine of 2.1. (Normal results are 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women.) The emergency department physician did not address metFORMIN. The patient was hydrated and discharged. Discharge instructions for patient instructed patient to continue metFORMIN.

A physician identified a Tapazole® [methimazole] and Synthroid® [levothyroxine] drug interaction. The admission orders were processed the previous night which included both Synthroid and Tapazole. The interaction did not flag [in the order entry system] and was missed. Pharmacy investigated and found that the computer master inventory entry for Synthroid was missing [appropriate] codes. Thus, Synthroid was not flagging for therapeutic duplications, drug interactions, etc. The physician discontinued Tapazole. Pharmacy updated the entry for Synthroid to reflect the proper coding.

The patient was prescribed fluconazole by an orthopedic surgeon after consulting with infections disease. The patient is s/p [status post] renal transplant and taking Prograf® [tacrolimus]. The patient was admitted and Prograf was held till creatinine and tacrolimus levels returned within normal limits.

Therapeutic Duplications

Nearly a quarter (22.2%, n = 181 of 815) of reports were identified as involving therapeutic duplications. Therapeutic duplication events reached patients in 65.2% (n = 118 of 181) of the reports. Only 2.2% (n = 4) of the events were reported as Serious Events (harm score E and F; see Figure 2).

Elderly patients were involved in most (60.2%, n = 109) of these events (see Figure 3).

Therapeutic duplications occurred in 36 unique patient care areas with pharmacy (27.1%, n = 49 of 181) cited most often. Medical/surgical and telemetry units were involved in 13.3% (n = 24) and 11.6% (n = 21) of the events, respectively.

Overall, 78 unique medications were mentioned. The most common medications were anticoagulants, a class of high-alert medications,5 including heparin (47%, n = 85 of 181), enoxaparin (34.8%, n = 63), rivaroxaban (13.3%, n = 24) and dabigatran (11%, n = 20). The most common pairs of medications were combinations of anticoagulants (Figure 5). Overall, anticoagulants were mentioned 215 times (more than one anticoagulant was mentioned in some reports) in 181 reports.

Figure 5. Most Common Pairs* Involved in Drug-Drug Interaction Reports Identified as Therapeutic Duplications, as Reported to the Pennsylvania Patient Safety Authority, April 2009 through March 2016 (n = 181)

Figure 5. Most Common Pairs Involved in Drug-Drug Interaction Reports Identified as Therapeutic Duplications* These drug pairs consist of anticoagulants, a class of high-alert medications.

Following are examples of reported therapeutic duplications that reached patients:

The patient received 3 doses of Lovenox® [enoxaparin] and 2 doses of heparin in a 24-hour period. A physician ordered Lovenox and did not discontinue heparin patient was already receiving. Pharmacy did not note warning when Lovenox was entered into the pharmacy computer. Nurses did not clarify order on when to give Lovenox and gave both Lovenox and heparin at the same time. Patient sent to acute care for possible GI [gastrointestinal] bleed.

Patient presented in hypertensive emergency and was started on IV furosemide, IV nitroglycerin, and IV nicardipine. The next day, the patient was being transitioned back to his home oral medication regimen. The patient was given some of his home medications while the nicardipine was still running and he became severely hypotensive requiring cardiovascular support. He was discharged home a week later with no further complications.

Upon admission to the hospital the home medication list was obtained and verified with the patient. The patient stated that he was taking captopril 50 mg TID [three times a day] and lisinopril 5 mg daily. The medication reconciliation list was printed and both orders were profiled. The pharmacist did not catch the therapeutic duplication. Both medications were sent and both were administered. The patients experienced a rise in potassium to greater than 5.0, which sent an alert to pharmacy concerning the ACE [angiotensin-converting enzyme] inhibitors. The pharmacist called the physician and received an order to discontinue the captopril and continue the lisinopril.

Drug Contraindications

Drugs may be contraindicated when the benefit of the combination of a drug and another drug, comorbid condition, or procedure does not outweigh the risk (e.g., aspirin is relatively contraindicated for children with viral infections because it increases the risk of Reye’s syndrome). Drug contraindications accounted for 8.1% (n = 66 of 815) of events. Reports involving drug contraindications were categorized by harm score with 68.2% (n = 45 of 66) of the events reaching the patient (harm score C through I). Only 3% (n = 2) were reported as Serious Events with patient harm (harm score E and F; see Figure 2).

Most (56.1%, n = 37 of 66) of these events involved an adult patient, but 42.4% (n = 28) of events involved elderly patients (see Figure 3).

Thirty-three unique patient care areas were associated with drug contraindication events with medical/surgical units (13.6%, n = 9), pharmacy (10.6%, n = 7), and telemetry (10.6%, n = 7) the top cited care areas.

Fifty-six unique medications and 21 unique pairs of medications were cited in reports. The most common medications mentioned in reports included nitroglycerin (12.1%, n = 8 of 66) and enoxaparin (9.1%, n = 6). The most common pairs of medications included nitroglycerin and sildenafil (10.6%, n = 7), methadone with nalbuphine (7.6%, n = 5), and dofetilide with sulfamethoxazole/trimethoprim (4.5%, n = 3).

There was a variety of contraindications to drug therapy, with the most common involving drug-drug contraindications (51.5%, n = 34). Contraindications due to allergies were involved in 15.2% (n = 10 of 66) and contraindications to a therapeutic intervention (e.g., administration of an anticoagulant with an epidural line in place) were involved in 12.1% (n = 8) of the reported events (see Table).

​​Table. Most Common Drug Contraindications, as Reported to the Pennsylvania Patient Safety Authority, April 2009 through March 2016 (n = 66)
Event Type No. of Reports %
Drug-drug3451.5
Allergy1015.2
Therapeutic intervention812.1
Laboratory values710.6
Diagnosis57.6
Test11.5
Procedure11.5

 

Following are examples of reported drug contraindications that reached patients:

Patient who was pregnant and on methadone for opioid addiction was admitted to rule out sepsis. Nalbuphine ordered by resident, order processed, filled and administered to patient. Directly after the dose was administered, the patient began to exhibit signs of withdrawal (i.e. tachycardia, pain, n/v [nausea and vomiting], cramps). The fetus was also tachycardic. Patient was transferred. Morphine was administered and symptoms abated. Length of stay increased by one day for monitoring.

I verified an order to discontinue isosorbide mononitrate extended release 30 mg QAM [every morning]. Upon further profile review, I noticed the patient was also on sildenafil 20 mg PO [by mouth] TID. Isosorbide mononitrate and sildenafil were verified three days earlier. It is unclear whether the pharmacist verifying sildenafil spoke with physician about the contraindication between [sildenafil and] isosorbide mononitrate.

Patient was seen in urology clinic and started on ciprofloxacin and Bactrim™ [sulfamethoxazole and trimethoprim]. Unfortunately, Bactrim is contraindicated with the patient’s Tikosyn® [dofetilide] therapy. Patient was doing okay on therapy but was admitted for arrhythmia evaluation which did not reveal anything. Bactrim therapy stopped after consultation with urology. Patient reeducated on drug interactions. Unfortunately, patient used two pharmacies and the insurance company did not alert the outpatient pharmacy.

_______________

* The details of the PA-PSRS event narratives in this article have been modified to preserve confidentiality.

Discussion

Information regarding the mechanisms of drug incompatibilities is extensive, but quantitative information on the frequency of occurrence and significance in a clinical setting is limited. In one study, incompatibilities were investigated in a pediatric intensive care ward showing that 3.4 % of drug combinations were incompatible and thus potentially dangerous.6 Tissot et al. found that 26% of incompatibilities in an ICU were life threatening.7 Another study collected 78 different medication regimens and found 15% with incompatibility reactions.8

It is important to understand that there are many instances when two or more medications have to be given concurrently, but that does not mean that they are compatible with each other. For example, the Institute for Safe Medication Practices (ISMP) reported that a pharmacist who was asked whether reteplase injection could be infused with heparin consulted the product package insert, which stated that heparin frequently has been given concomitantly with reteplase.9 Thus, the patient received both drugs through the same IV line. Unfortunately, the pharmacist missed a sentence that appeared four lines above the information he had read that indicated heparin and reteplase are incompatible when combined in solution and should not be administered together through the same IV line. (Together, the drugs react to form a mass of solid or semi-solid material, which can stop the infusion. Heparin and reteplase can be given simultaneously but never mixed within the same container.)

Kanji et al. performed a systematic review to qualify and quantify the physical and chemical stability data published for commonly used continuously infused medications in ICU.10 The authors found 93 studies; 86 (92%) studies evaluated physical compatibility and 35 (38%) studies evaluated chemical compatibility of at least one drug combination of interest. Physical and/or chemical compatibility data existed for only 441 (54%) of the possible 820 two-drug combinations, whereas chemical compatibility data existed for only 75 (9%) of the possible combinations. Of the 441 combinations for which compatibility data were available, 67 (15%) represented incompatible combinations and 39 (9%) had conflicting information, with both compatible and incompatible data identified. The authors concluded that physical compatibility studies are lacking for commonly used medications in ICU patients and may contribute to unsafe medication practices. This is important because patients who are critically ill may require multiple IV medications administered by continuous infusion. Obtaining separate venous access sites for each drug infusion would be ideal, but in actuality, the number of drug infusions often surpasses the available access sites.

While many new drugs are approved by the U.S. Food and Drug Administration (FDA) each year, research involving incompatibilities has decreased. In 1991 and 1992, there were 245 newly published clinical pharmaceutics research articles incorporated into the seventh edition of Trissel’s Handbook on Injectable Drugs.11 Most of the studies came from U.S. researchers in academia, pharmacy practice, and pharmacy students performing laboratory-based research. Twenty years later, Trissel noted that the 17th edition of the Handbook on Injectable Drugs incorporated fewer than 45 new research articles, most from foreign researchers. In other words, over a twenty-year span, new research studies of drug compatibility and stability have declined more than 80%.

The use of electronic order entry systems with clinical decision support are among the most promising strategies for detecting and possibly preventing medication errors, including drug-drug interactions. However, they have not yet been tested with respect to preventing incompatibilities.12,13 To render a meaningful alert, electronic decision support systems would require, in addition to the drug name, dose, and so on, input on the number of available IV lines and the drugs currently being delivered into a given lumen.14 This type of information is not routinely available in ICU patient records, much less in a structured format that would enable electronic screening.

DDIs that reach the patient can largely be considered preventable. One study reports that 9% of medication-related errors are likely due to DDIs.15 In a study that assessed the prevalence of 25 clinically important DDIs in the ambulatory care clinics of the Department of Veterans Affairs, the authors found an overall rate of 2.15% for potential DDIs.16 Case exposure rates were greatest for patients receiving selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs), ganciclovir and zidovudine, anticoagulants and thyroid hormones, and warfarin and nonsteroidal anti-inflammatory drugs. With new drugs coming on the market each year, the potential for DDIs to take place will only increase. In fact, more than a decade ago, Hansten noted that more than 15,000 articles related to DDIs had been published.17

Much has been written about the use of an alerting mechanism to make prescribers and pharmacists aware of the potential for a DDI, therapeutic duplication, or contraindication while also acknowledging concerns for alert fatigue. Although alerts may be overused, relying on practitioner diligence to catch drug interactions can be unreliable, especially when there are many drugs approved by the FDA each year. Studies have shown that pharmacists and soon-to-graduate pharmacy students identified only 66% and 68% of the potential interactions.18,19 Weideman et al. noted that none of the pharmacists were able to detect all potential interactions in a profile containing 8 or 16 drugs.19 This reinforces the notion that a variety of risk reduction strategies targeting system-based causes of error, rather than relying solely on human performance, is required to intercept drug interaction and other medication errors.

The most common pair of medications involved in DDIs reported to the Authority was IV contrast and metFORMIN. The most significant adverse effect of metFORMIN therapy is the potential for the development of metFORMIN-associated lactic acidosis, particularly in susceptible patients. Because metFORMIN is excreted by the kidneys, any patient with existing renal insufficiencies are more prone to these effects. Iodinated contrast agents are also eliminated by the kidneys, thus the combination of both products could be a concern. Originally, when metFORMIN was introduced to the market, the risk of acute kidney injury and metFORMIN-associated lactic acidosis led to recommendation for facilities to establish a process to “hold” metFORMIN before or after IV contrast was administered to all patients. However, both FDA and the American College of Radiology (ACR) have updated recommendations that restrict the need to discontinue metFORMIN to only certain patient populations20,21 (see Concomitant Use of metFORMIN and IV Iodinated Contrast).

Limitations

In-depth analysis by the Authority of Serious Events resulting from medication prescribing errors is limited by the information reported through PA-PSRS, including the event descriptions. As with all reporting systems, the type and number of reports collected depend on the degree to which facility reporting is accurate and complete. Information about underlying patient conditions, which may have impacted events, was not consistently available. Information regarding the adoption and use of computerized prescriber order entry systems and clinical decision support by the reporting facilities was also unavailable.

Risk Reduction Strategies

The occurrence and perpetuation of drug interactions involve many stages in the medication use process. This starts with identifying possible interacting drugs when obtaining a medication list during the medication reconciliation process upon patients’ admission to a facility. It includes reviewing the medication profile, prescribing medications, and pharmacy review of ordered medications. The medication use process also involves communicating to resolve clinically significant drug combinations and communicating relevant interactions to prescribers or nursing (e.g., to possibly alter the timing of administration of one of the offending drugs). It extends to monitoring patients for the possible adverse effects. Finally, it requires educating patients upon discharge.

Efforts to prevent harm from these types of drug interactions can be focused on either reducing the occurrence of potential interactions before they happen or mitigating the risk of adverse outcomes associated with interactions that reach the patient. The following strategies may be useful to healthcare facilities seeking to reduce drug interaction events.

Drug Incompatibilities

  • Ensure drug information resources are available and up to date for prescribers, pharmacy, and nursing staff to assess for potential incompatibilities.
  • When determining the compatibility between two drugs, it is important to also evaluate the type of tubing being used for IV administration or whether the drugs might be combined into one syringe. For example, when a drug is incompatible with other intravenous medications, tubing used for administration sets should not have a Y connector for flushing the line or piggyback drug administration.22
  • If incompatible drugs must be given sequentially through the same line, flush the line adequately with saline or other compatible solution between the drugs.9
  • Standardize the concentration and diluent of continuously administered IV drugs. In an attempt to minimize the risk of incompatibilities in an anesthesia ICU, the authors of one study built upon their drug standardization process and grouped the drugs according to pH, medical indication, and chemical structure.23 The ICU staff decided to use multi-lumen central venous catheters, and each group of drugs was assigned to one lumen. Only drugs that belonged to the same group were infused simultaneously through the same lumen; therefore, intragroup incompatibilities were excluded before establishing a new drug administration plan at the ICU. In that study, the visual compatibility of 115 clinically reasonable intragroup drug mixtures was investigated. All drug combinations were compatible for six hours except mixtures containing thiopental, which was reassigned to a single-line use.
  • The use of in-line filters can reduce the risk of precipitates or particles, which result from incompatibilities, entering the body. As a consequence, the filter may become blocked if precipitation occurs. A blocked filter should signal the need to investigate the situation and check the medications ordered to eliminate any incompatibility.24

Drug-Drug Interaction, Therapeutic Duplication, and Contraindication

  • Avoid the combination of interacting medications when possible. However, some combinations of drug may be clinically necessary even with the potential for unfavorable outcomes associated with their combined use.
  • Explore the possibility of adjusting the dose of the object drug (i.e., the drug that is altered by the interaction) to decrease the risks from the drug interaction if concomitant use of the drugs is necessary.25
  • Space dosing times of drugs to avoid an interaction.25 For example, some drug interactions involve drugs binding in the GI tract. These types of interactions can be avoided if the interacting drug is administered at least two hours before or four hours after the other drug. This allows the interacting drug to be absorbed before the second drug is introduced.
  • Refine and improve drug-interaction alerts. When practitioners become accustomed to clinically unimportant or irrelevant warnings, they often ignore or bypass these “false alarms.”26 Fortunately, there are strategies that can help optimize the effectiveness of alerts.
    • Use a tiered system for interactive warnings to allow staff to view and easily bypass less serious issues if appropriate, but require staff to make a text entry to describe the rationale for overriding significant alerts.26 To further enhance the effectiveness of this tiered system, work to reduce the frequency of warnings that are not clinically significant to users.27 Engage frontline staff who repeatedly encounter clinical warnings in this effort, because they can help identify alerts that are not clinically significant.
    • Once insignificant warnings have been reduced, organizations may want to display the highest-level alerts (e.g., contraindications, severe DDI) and lower-level alerts (e.g., warnings, precautions) for pharmacists, but display only the highest level for prescribers.27
    • Create and regularly update a list of significant alerts that require direct prescriber notification. The use of such a list can help guide appropriate communication of and response to a significant alert.26
    • Ask prescribers and pharmacists who enter orders to note warnings that they feel are not clinically significant.26 Then, evaluate the severity level of these less significant warnings and adjust as necessary to minimize potential for overlooking more clinically significant warnings.
    • Many systems can provide reports about all warnings that have been overridden.26 Assign a clinician or manager to review the report daily to identify any problems. Consider focusing on a small number of common but critically important warnings to monitor the effectiveness of the computer’s alert system.
    • Work with the drug information vendor to build or modify the severity of alerts necessary to warn practitioners about possible serious or fatal adverse events, especially those for certain conditions (e.g., drugs that prolong the cardiac QT interval).27 Keep in mind that the time to build custom alerts varies depending on the technology in use and expertise of staff.
    • Establish a system to gather and document all comorbid conditions in a structured diagnosis or problem list field in the electronic health record (EHR).27 Link this information to the prescriber and pharmacy order entry systems to promote clinical screening when new drugs are prescribed, to detect potential contraindications to those drugs.
  • Monitor patients for early detection of possible interactions and adverse effects.25 When it is necessary to administer a pair of drugs that interact with one another, the interaction might be managed through close laboratory or clinical monitoring. If evidence that an interaction is occurring, healthcare practitioners will be able make appropriate dosage changes or even discontinue the drug(s) if necessary.
  • Use the Computerized Prescriber Order Entry (CPOE) System Evaluation Toolkit, available from the Authority, to test the CPOE system to see if potentially harmful drug-drug interactions or drug contraindications are detected.
  • Notify prescribers and pharmacists of any changes (e.g., types of alerts not available or turned off) made to the alerting system in the order entry systems.27
  • Although technology can help improve patient outcomes, educate and then remind staff to avoid total reliance on any technology involved in the medication-use process and that it should be one part of a well-integrated set of safety strategies.27
  • Establish a process to educate staff on new and potentially serious drug interactions identified in the literature or by FDA.

Conclusion

Review of events submitted to the Authority shows that the medication use processes associated with the occurrence of drug interactions needs to be assessed and improved. Interactions may pose a significant risk to patients’ health. Effective identification and preventive strategies need to include all stages of the medication use process to prevent harm to patients from the administration of multiple medications.

Notes

  1. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995 Oct 9;155(18):1949-56.
  2. Thomas A, Routledge PA. Drug interactions in clinical practice. Focus Pharmacovigilance Bull 2003:1-7.
  3. Kanji S, Lam J, Goddard RD, et al. Cross-sectional observational study of continuously infused medication administration practices and venous access devices in Canadian adult ICU patients. Crit Care Med 2008;36(Suppl):A94.
  4. National Coordinating Council for Medication Error Reporting and Prevention. NCC MERP index for categorizing medication errors [online]. 2001 Feb [cited 2016 Aug 4]. http://www.nccmerp.org/types-medication-errors
  5. Institute for Safe Medication Practices. ISMP list of high-alert medications in acute care settings [online]. 2014 [cited 2015 Aug 4]. http://www.ismp.org/Tools/institutionalhighAlert.asp
  6. Gikic M, Di Paolo ER, Pannatier A, et al. Evaluation of physicochemical incompatibilities during parenteral drug administration in a paediatric intensive care unit. Pharm World Sci 2000 Jun;22(3): 88-91.
  7. Tissot E, Cornette C, Demoly P, et al. Medication errors at the administration stage in an intensive care unit. Intensive Care Med 1999 Apr;25(4):3539.
  8. Vogel Kahmann I, Bürki R, Denzler U, et al. Incompatibility reactions in the intensive care unit. Five years after the implementation of a simple “colour code system.” Anaesthesist 2003 May;52(5):409-12.
  9. Institute for Safe Medication Practices. Safety Brief. ISMP Med Saf Alert Acute Care 2000 Feb 23;5(4):1.
  10. Kanji S, Lam J, Johanson C., et al. Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units. Crit Care Med 2010 Sep;38(9):1890-8.
  11. Institute for Safe Medication Practices. Cheers honoree’s acceptance speech creates pause for reflection. ISMP Med Saf Alert Acute Care 2012 May 3;17(9):1-3.
  12. Bates DW, Leape LL, Cullen DJ, et al. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA 1998 Oct 21;280(15):1311-6.
  13. Bates, DW, Teich JM, Lee J, et al. The impact of computerized physician order entry on medication error prevention. J Am Med Inform Assoc 1999 Jul-Aug;6(4):313-21.
  14. Bertsche T, Mayer Y, Stahl R, et al. Prevention of intravenous drug incompatibilities in an intensive care unit. Am J Health-Syst Pharm 2008 Oct 1;65(19):1834-40.
  15. Leape LL, Bates DW, Cullen DJ et al. Systems analysis of adverse drug events. ADE prevention study group. JAMA 1995 Jul 5;274(1):35-43.
  16. Mahmood M, Malone DC, Skrepnek GH, et al. Potential drug-drug interactions within Veterans Affairs medical centers. Am J Health Syst Pharm 2007 Jul 15;64(14):1500-5.
  17. Hansten PD. Drug interaction management. Pharm World Sci 2003 June;25(3):94-7.
  18. Cavuto NJ, Woosley RL, Sale M. Pharmacies and prevention of potentially fatal drug interactions. JAMA 1996 Apr 10;275(14):1086-7.
  19. Weideman R, Bernstein I, McKinney W. Pharmacist recognition of potential drug interactions. Am J Health-Syst Pharm 1999 Aug 1;56(15):1524-9.
  20. U.S. Food and Drug Administration. FDA drug safety announcement: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function [online]. 2016 Apr 8 [cited 2016 Aug 4]. http://www.fda.gov/drugs/drugsafety/ucm493244.htm
  21. American College of Radiology. Metformin [online]. Chapter 10. In: ACR Manual on Contrast Media. Version 10.2. 2016 [cited 2016 Aug 4]. http://www.acr.org/quality-safety/resources/contrast-manual
  22. Institute for Safe Medication Practices. Don’t use epidural tubing for an IV solution. ISMP Med Saf Alert Acute Care 2008 Jan 17;13(1):3.
  23. Nemec K, Kopelent-Frank H, Greif R. Standardization of infusion solutions to reduce the risk of incompatibilities. Am J Health Syst Pharm 2008 Sep 1;65(17):1648-54
  24. Ball PA. Intravenous in-line filters: filtering the evidence. Curr Opin Clin Nutr Metab Care 2003 May;6(3):319-25. Also available at https://www.researchgate.net/publication/10809860_Intravenous_in-line_filters_Filtering_the_evidence
  25. Ansari J. Drug interaction and pharmacist. J Young Pharm 2010 Jul-Aug;2(3);326-31.
  26. Institute for Safe Medication Practices. Optimizing the use of computer system clinical alerts. ISMP Med Saf Alert Acute Care 2000 Jan 26;5(2):1.
  27. Institute for Safe Medication Practices. The absence of a drug-disease interaction alert leads to a child’s death. ISMP Med Saf Alert Acute Care 2015 May 21;20(10):1-4. Also available at http://www.ismp.org/Newsletters/acutecare/showarticle.aspx?id=109

Supplementary Material

Concomitant Use of metFORMIN and IV Iodinated Contrast

In the past, guidelines and drug labelling called for doses of metFORMIN to be held before patients receive any type of iodinated contrast media. The reason cited for this was an increased risk of acute kidney injury (AKI) and lactic acidosis. However, no cases of lactic acidosis have been reported after intravenous (IV) iodinated contrast medium in patients without a contraindication to metFORMIN therapy (e.g., patients with normal renal function). Upon review of recent studies and current evidence, the U.S. Food and Drug Administration (FDA) and the American College of Radiology (ACR) have updated guidelines for concurrent use of metFORMIN and iodinated contrast media. In April 2016, FDA revised the labelling requirements for metFORMIN products to include recommendations to discontinue use of metFORMIN prior to administering IV iodinated contrast to patients with estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73m2 or with a history of liver disease, alcoholism, or heart failure.1 (Normal levels for eGFR are from 90 to 120 mL/min/1.73 m2.) Then, in May 2016, ACR updated its guidelines, stating there is no need to discontinue metFORMIN prior to IV iodinated contrast in patients with no signs of AKI with eGFR greater than 30 mL/min/1.73m2.2 It is still recommended to discontinue metFORMIN if a patient is to receive intra-arterial iodinated contrast.1,2 Please see both the FDA and ACR updates for complete guidance and recommendations. 

Notes

  1. U.S. Food and Drug Administration. FDA drug safety announcement: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function [online]. 2016 Apr 8 [cited 2016 Aug 4]. http://www.fda.gov/drugs/drugsafety/ucm493244.htm
  2. American College of Radiology. Metformin [online]. Chapter 10. In: ACR Manual on Contrast Media. Version 10.2. 2016 [cited 2016 Aug 4]. http://www.acr.org/quality-safety/resources/contrast-manual

Self-Assessment Questions

The following questions about this article may be useful for internal education and assessment. You may use the following examples or develop your own questions.

Learning Objectives
  • Identify the most common types of drug interactions, as reported to the Pennsylvania Patient Safety Authority.
  • Identify the most common drug pairs involved in drug interactions, as reported to the Authority.
  • Identify the mechanisms and potential outcomes for drug interactions.
  • Assess risk reduction strategies that can be implemented to help prevent drug interactions.
Questions
  1. Which of the following type of drug interaction was most frequently reported to the Authority as a Serious Event?
    1. Drug-drug interactions
    2. Drug incompatibilities
    3. Therapeutic duplications
    4. Drug contraindications
    5. Drug-food interactions
  2. Which of the following drug pairs involved in drug incompatibilities was the most commonly reported?
    1. Heparin and vancomycin
    2. Ciprofloxacin and IV fluids with electrolytes
    3. CefTRIAXone and lactated Ringer's solution
    4. Heparin and amiodarone
    5. Pantoprazole and IV fluids
  3. Which of the following drug pairs involved in therapeutic duplications was the most commonly reported?
    1. Heparin and dabigatran
    2. Heparin and rivaroxaban
    3. Enoxaparin and rivaroxaban
    4. Heparin and enoxaparin
    5. Heparin and apixaban
  4. Which of the following statements about drug interactions is FALSE?
    1. Drug interactions may occur inside (drug-drug interactions) or outside (drug incompatibilities) the body.
    2. Drug-drug interactions may result from pharmacokinetic interactions or from interactions at drug receptors.
    3. A drug incompatibility occurs when two or more injectable drugs are mixed and the stability or structure of the drugs is altered by physical or chemical reactions.
    4. The pharmacological effect of a drug interaction of one or both drugs may be increased or decreased, but rarely results in an adverse effect.
    5. Physical changes from drug incompatibilities may lead to precipitate formation that can cause catheter occlusion and embolism and can contribute to a range of adverse drug events (ADEs), from thrombophlebitis to multi-organ failure.
  5. Which of the following statements about the use of metFORMIN and IV contrast is FALSE?
    1. The most common pair of medications involved in drug-drug interactions reported to the Authority was IV contrast and metFORMIN.
    2. The most significant adverse effect of metFORMIN therapy is the potential for developing metFORMIN-associated lactic acidosis, particularly in susceptible patients.
    3. Because metFORMIN is excreted by the kidneys, patients with existing renal insufficiencies are more prone to adverse effects.
    4. According the U.S. Food and Drug Administration (FDA) and American College of Radiology (ACR), facilities should establish a process to “hold” metFORMIN before or after IV contrast is administered to all patients.

Questions 6 refers to the following case:

A patient had an order for one liter of sodium chloride 0.9% to be given, as well as an order for oxaliplatin. The sodium chloride was run at a Y-site connection that was closest to the patient for the last hour of the infusion. After the infusion was completed, the patient was transferred to radiation therapy, where she developed rigors. The patient was treated with diphenhydrAMINE and famotidine for likely incompatibility reaction with the sodium chloride.

  1. Which of the following risk reduction strategies would NOT help prevent this drug incompatibility?
    1. Ensure drug information resources are available and up to date for prescribers, pharmacy, and nursing staff to assess for potential incompatibilities.
    2. If incompatible drugs must be given sequentially through the same line, flush the line adequately with saline or other compatible solution after both drugs have been infused.
    3. When determining the compatibility between two drugs, evaluate the type of tubing being used for IV administration or whether the drugs might be combined into one syringe.
    4. Use in-line filters to reduce the risk of precipitates or particles, which result from incompatibilities, entering the body.

Questions 7 refers to the following case:

An order was received in the pharmacy for a patient for amiodarone 400 mg twice a day. This patient had previously received an order for fluconazole 100 mg daily and warfarin 5 mg daily by different physicians. The computer system generated two interaction warnings involving amiodarone, one for warfarin, and a second warning for fluconazole. The orders were allowed to become active, and the pharmacist did not enter any clinical interventions indicating that the physician was questioned on either one. After discharge, the patient attempted to get prescriptions for amiodarone and fluconazole filled at a retail pharmacy and was notified of interaction.

  1. Which of the following risk-reduction strategies would NOT help prevent this drug interaction?
    1. Avoid the combination of interacting medications when possible.
    2. Explore the possibility of adjusting the dose of the object drug (i.e., the drug that is altered by the interaction) to decrease the risks from the drug interaction if concomitant use of the drugs is necessary.
    3. Space dosing times of drugs to avoid an interaction to allow the interacting drug to be absorbed before the second drug is introduced.
    4. Use a system for interactive warnings to allow staff to view and easily bypass significant alerts.
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